Methods for manufacturing non-glass prefilled syringes

ABSTRACT

A method of sterilizing a prefilled syringe comprises assembling a syringe assembly and performing at least one ethylene oxide (EtO) sterilization procedure cycle. The assembling step includes inserting a tip cap at a first end of a plunger, filling a non-glass barrel with sterilization sensitive material at a second end of the barrel, and inserting the plunger into the barrel at a second end to seal the sterilization sensitive material within the barrel. The EtO sterilization procedure cycle comprises undergoing a preprocessing stage, a wash and conditioning stage, an EtO sterilization stage and a wash and post exposure stage. Upon completing the EtO sterilization procedure cycle, a resultant pH of the sterilization-sensitive material does not exceed an acceptable pH range as defined by the United States Pharmacopeia. The disclosure also discusses inserting an assembled prefilled syringe into a procedure tray prior to performing the EtO sterilization procedure cycle.

FIELD OF TECHNOLOGY

The present disclosure relates to ethylene oxide (“EtO”) gassterilization methods for sterilizing non-glass containers that are atleast partially prefilled with material that is sensitive tosterilization techniques including, but not limited to, containersprefilled with saline (0.9% NaCl saline, heparinized saline, orlidocaine), without causing EtO ingress gas ingress into the prefilledcontainer.

BACKGROUND

Syringes have been in use for many years. However, syringes weretypically made of glass. Gradually with the discovery of plasticmaterials, some syringes began to be offered in plastic. In recenthistory, a number of plastic syringe manufacturers, medical devicemanufacturers and/or drug companies began offering prefilled plasticcontainers, including vials and syringes, with fluid material, such assaline, heparinized saline or lidocaine. However, as discovered by thesyringe manufacturers these materials are sensitive to certainsterilization techniques. For example, IV flush solutions, drugs,vaccines or other fluid materials that contain saline solution mayexperience a change in their respective composition or properties, suchas an undesirable pH shift of the saline solution, when saline contentsin the plastic container is exposed to ethylene oxide (“EtO”) gassterilization. Further, the potency of heparinized saline and/orlidocaine may be adversely affected, and EtO gas residual, and/orresidual toxic byproducts may be created when the solution is exposed tocertain sterilization techniques after filling is accomplished.

Pre-filled syringes manufactured from plastic materials, such aspolypropylene have been found to lead to various complications. Forexample, the United States Pharmacopeia (“USP”) guidelines require thatnormal saline solution (i.e., 0.9% NaCl) in prefilled syringes may onlypossess a pH between 4.5 and 7.0 to be suitable for human use. It hasbeen determined that one complication that frequently occurs with knownprefilled containers is an undesired shift in pH following ethyleneoxide gas (EtO) sterilization. PH has been identified as an indicator ofEO ingress, such that if the pH of the fluid within the syringe hadshifted (usually +, or higher) outside of accepted USP standards limits,one or more of the other parameters indicative of suitable for human use(as discussed in further detail below), were also exceeded.

Commercially available prior art prefilled saline and heparinized salinesyringes and a vial for IV flushes were obtained for a testing regimenperformed and designed for assess state of the art for prefilled plasticcontainers, such as syringes and vials. Tests were performed on controlsamples that had not be subjected to EtO sterilization, as well as on 11groups of EtO sterilized samples. Upon completion of the EtOsterilization process, the pH level of all of the samples were tested.The tests revealed that the commercially available samples demonstratedan undesirable pH shift, such that the pH of the saline exceeds therange permitted by the USP after being subjected to EtO sterilization.Each of the test groups subjected 10 samples from different prior artmanufacturers. The average amount of pH shift from the control samplesindicated unacceptable pH shifts, which resulted in the pH of the salinefalling outside of the mandated pH range of 4.5 to 7.0:

Avg. fluid pH shift Test Syringe (from controls) Prior Art Group 1 +3.87Prior Art Group 2 +3.97 Prior Art Group 3 +4.49 Prior Art Group 4 +5.27Prior Art Group 5 +4.10 Prior Art Group 6 +4.26 Prior Art Group 7 +4.45Prior Art Group 8 +4.96 Prior Art Group 9 +4.74 Prior Art Group 10 +4.99Prior Art Group 11 +4.51

This undesirable shift is determinative of EO ingress into thesyringe/container, during the EtO sterilization process.

However, it is desirable to package prefilled syringes containingsterilization-sensitive fluid material with other medical proceduraltools and/or equipment requiring sterilization in a medical proceduraltray, kit, pouch or other packaging. For example, collectively packagedconvenience kits such as surgical or procedural kits may includeprefilled syringes, as well as surgical instruments, gloves, dressings,aseptic wipes, etc.—all requiring EtO sterilization, which are necessaryto perform a given medical procedure. In such instances where prefilledsyringes that include sterilization-sensitive fluid material areincorporated in such convenience kits, one known way to avoid theproblems created by the use of plastic pre-filled syringes is to utilizeglass containers and glass syringes due to the barrier properties ofglass, as glass effectively prevents the above identified undesirableeffects of EtO ingress to the fluid material.

However, while glass containers have proven to be a suitable barrier forenabling EtO sterilization, glass containers have certain limitationsthat leave this choice of material undesirable. As one example, glasscontainers are fragile. As a result, there is a danger of thesterilization-sensitive material attacking the surface of the glassmaterial, or that the glass may sliver and contaminate the materialtherein. As another example, microcracks in the glass may permitpenetration of EO and/or the glass container may explode during deepsterilization cycle vacuums. Other issues caused by the fragility of theglass include breakage of the syringe if the syringe is dropped. Whilebroken glass may be cleaned up, if the syringe is dropped during aprocedure in the operating room, such clean-up might require shuttingthe operating room down (at significant financial cost to the facility)to recreate a sterile field, as well as delaying patient care. Further,glass is much more costly to manufacture as compared to plastic, and hasinherent limitations relating to geometry, size and intricacy of thecontainer. Transporting glass, including with sterilization sensitivematerial therein and transporting used glass syringes after use, is muchmore expensive than plastic due to the weight of the material, inaddition to the extra care that must be taken to avoid breakage.Finally, glass syringes have additional issues, in that an integratedmedical industry standard luer tip cannot be created for a glasssyringe. Instead, an adapter must also be provided to incorporate a luerfitting, thereby increasing costs.

One method of addressing the known EtO sterilization limits inherent toplastic containers is to sterilize an empty plastic syringe and thenfill the plastic syringe with sterile fluid (introducing the sterilefluid in a clean room or aseptic environment). The filled syringe isthen packaged in a non-sterile pouch. This method provides a “sterilefluid pathway” but the syringe exterior itself is not sterile. Morespecifically, the outside of the syringe is not sterile. As a result,the syringe must be separately packaged from the rest of the procedurekit, thereby creating two different SKU numbers, which may complicateinventory tracking and create end clinical user inconvenience andinefficiency. In one example, the non-sterile, prefilled container isattached to the exterior of a sterile kit post-sterilization of the kit,sometimes referred to as a “sidecar” package, thereby creating asecondary non-sterile kit comprised of a non-sterile prefilled containerand a sterile kit. While this combination kit may reduce inventorytracking, the added step of separately packaging plastic containers andattaching them to sterilized kits makes manufacturing and assembly moretime consuming and expensive. In addition, there is a danger that thesidecar package may become detached and lost in the medical facility,which then may result in unnecessary waste, as well as delaying theprocedure while new material is located.

In addition, for a fully wrapped “liftout” surgical kit of componentsinside of a sterile tray, the syringe components are not inside thewrapped assemblies. Instead, these syringe components must be separatelyunpackaged and loaded onto the surgical wrap/drape, after the wrap/drapeis opened within the sterile field.

Another known method to address known EtO sterilization limits inherentto plastic containers is to fill an empty plastic syringe with fluidmaterial, which may be introduced as sterile fluid in a clean room oraseptic environment, as discussed above. The filled plastic syringe maythen be autoclaved, which will ensure that a sterile fluid and fluidpathway results. However, the outside of the syringe still remainsnon-sterile and may be packaged as described above.

Moreover, maintaining sterile technique during a clinical procedurebecomes more challenging when a separately packaged, non-sterilecomponent must be handled. This may affect the sequence of actionsrequired to complete a given procedure; or, in some cases, the number ofphysicians needed to complete a procedure. For example, during aprocedure, a nurse must open the non-sterile package outside of thesterile field and once the Doctor touches the syringe, the proceduremust be adjusted to maintain the sterile technique.

As another solution, a filled “sterile fluid path” syringe may be steamsterilized. Upon steam sterilization, the syringe is then placed in anEtO gas impermeable foil package, which is then introduced into aprocedural kit, with the kit and foil package being EtO sterilizedtogether. The foil package prevents the EtO gas inside the proceduralkit from getting through the foil package, and thus prevents EtO gasfrom interacting with the fluid material within the syringe. However,this process is also time consuming and expensive, as it requires twoseparate sterilization processes. Moreover, in use, it then requires aclinician to open multiple packages during a procedure and move it tothe appropriate location in the sterile field, as well as requiringproper disposal of the packaging components without compromising theintegrity of the sterile field.

In an another solution, the prefilled syringes containing sterilesolution (though the exterior of the syringe was not sterile), ispackaged in a sleeve that may be attached to lidding or a pouch of thekit. Once packaged, the sleeve may be autoclaved so that the packagedsyringe is sterile field ready. However, this arrangement then requiresan extra person to open the packaging to drop the syringe within thesterile field. This arrangement does not permit having the syringe in anEtO sterilizable procedure kit.

It is desired to address one or more such limitations experienced withknown glass containers, plastic containers, packaged kits, and/ormethods disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a side view of an exemplary syringe assembly;

FIG. 2 illustrates a cross-sectional view of the syringe assembly ofFIG. 1, taken along lines 2-2;

FIG. 3A illustrates side view of an exemplary plunger assembly for usewith the syringe assembly of FIG. 1;

FIG. 3B illustrates a side view of an exemplary plunger tip for use withthe plunger of FIG. 3A.

FIG. 4A illustrates a side view of a barrel of the exemplary syringeassembly of FIG. 1;

FIG. 4B illustrates an enlarged view of an exemplary barrel neck of thebarrel of FIG. 4A;

FIG. 4 C illustrates an enlarged view of an alternative arrangement of aproximal end of the barrel of FIG. 4A;

FIG. 5 illustrates a side view of an exemplary vial;

FIG. 6A illustrates a perspective view of a tip cap assembly;

FIG. 6B illustrates a perspective view of a tip cap insert of the tipcap assembly of FIG. 6A;

FIG. 7A is a cross-sectional view of the tip cap assembly of FIG. 6A;and

FIG. 7B is a plan view of the tip cap assembly of FIG. 7A; and

FIG. 8 is a flow chart illustrating various product flow paths forgroups of EtO sterilization processes.

DETAILED DESCRIPTION

Referring now to the drawings, illustrative examples are shown indetail. Although the drawings represent certain examples, the drawingsare not necessarily to scale and certain features may be exaggerated tobetter illustrate and explain an innovative aspect of an example.Further, the examples described herein are not intended to be exhaustiveor otherwise limiting to the precise form and configuration shown in thedrawings and disclosed herein.

A prefilled container system may include a syringe assembly having abarrel, plunger and tip cap. A chamber may be formed within the barrelbetween the plunger and tip cap and may be configured to holdsterilization sensitive materials such as saline or heparinized saline.The syringe assembly may be formed of various materials and/or solutionsthat permit the syringe assembly to be packaged with a surgical kitcontaining other items necessary to perform a medical procedure andsterilized together. For example, as determined by medical professionalssuch as nurses, surgeons and other operating room staff, such kits maybe tailored to particular procedures and may include items such asinstruments, drugs, antiseptics, dressings that are appropriate andneeded for the particular procedure. For convenience, as well as toreduce inventory burden (such as tracking) it is preferred thatindividual items not be separately packaged.

As another key advantage, providing a sterile convenience kit permitsoperating room staff to maintain established sterile techniques inperforming surgical operations, such that there is no need to separatelyremove the syringe from separate packaging and locate the syringe in thesterile field.

For health and sanitary purposes, it may be desired and necessary thatall items within the kit be sterilized and ready for use by the medicalprofessionals. During manufacturing, the items within the kit may besterilized to eliminate live bacteria or other microorganisms present onthe inside or outside of the kit, and inside and outside of anycomponent item within the sterile kit. Known sterilization methods mayinclude EtO sterilization, autoclaving, or other methods such asirradiation. In one embodiment, terminal sterilization is used as thesole sterilization step in the assembling and manufacturing of thepackaged kits. However, as explained above, the EtO gases used duringterminal sterilization may alter the composition of sterilizationsensitive material within a syringe.

Accordingly, a syringe assembly 100, as shown in FIG. 1, may include abarrel 105, a plunger 110 and a tip cap 115 (shown in FIG. 6A). Theinterior of the barrel 105 may cooperate with a distal end 113 of theplunger 110 and the tip cap 115, when assembled to the barrel 105, todefine a chamber 230 (best seen in FIG. 4A). Any number of solutions(i.e., material) may be included in the chamber 230. Examples ofpreferred solutions include, but are not limited to, sodium chloride(such as 0.9% NaCl saline), heparinized saline (various amounts ofheparin content), lidocaine or other liquid medication for infusion, orcatheter lumen line flushing. The solution may also include activeingredients such as vaccines, drugs, probiotics, diagnosticcompositions, etc. Typically, the chamber contents are a liquid solutionthat is sterile; either by an aseptic filling process or post fillingterminal sterilization that provides a sterile fluid path. Thesesolutions, when included in a procedural kit, may be adversely affectedby the terminal kit sterilization process, such as EtO sterilization asexplained above. However, the kit sterilization is necessary to ensureall the contents of the finished procedural kit are sterile.

The contents of plastic containers, as described above, may becompromised during the kit sterilization process and, therefore, thesolution contained therein may be affected and considered “sterilizationsensitive.” For example, EtO sterilization may include subjecting thefilled syringe assembly 100 to EtO gas. The use of EtO gas is effectiveand an accepted procedure to kill any micro-organisms and ensure thatthe assembly 100 is sterilized prior to use. However, as recognized byFederal Drug Administration (FDA), the EtO gases may alter thecomposition of the sterilization sensitive solution. Thus, as set out inthe notice of rulemaking published by the FDA in the Federal DrugAdministration, 43 Fed. Reg. 122 at 27474-27483 (proposed Jun. 23, 1978)(to be codified at 21 C.F.R. §221 and §821) (“Ethylene Oxide, EthyleneChlorohydrin, and Ethylene Glycol—Proposed Maximum Residue Limits andMaximum Levels of Exposure”) the contents of which are incorporated byreference in its entirety, the amount of residual Ethylene Oxide (EO)gas, Ethylene Chlorohydrin (ECH) and Ethylene Glycol (EG) toxicby-products present in an injectable drug must be tightly controlled.For injectable drugs, the FDA guidance document suggests that theresidual EO and ECH shall not exceed 10 ppm and the residual EG shallnot exceed 20 ppm. In addition, the FDA guidelines also set maximumdaily exposure level requirements. More specifically, for EO, themaximum daily exposure level is 30 μg/kg/day up to 30 days. For ECH, themaximum daily exposure level is 15 μg/kg/day up to 30 days. And for EG,the maximum daily exposure level is 2.5 mg/kg/day up to 30 days. Whilethe above proposed limits for residual EO, ECH and EG were neverpublished as a final rule, these limits have been used and accepted byboth industry and government as a de facto regulation for more almost 40years.

With specific reference to sodium chloride injections, the U.S.Pharmacopeia (USP)—National Formulary has provided a test standard foran acceptable pH in such solutions. More specifically, the pH should bein the range of 4.5-7.0 (test no. 791). The inventors of the presentapplication have determined that a pH shift outside of this range is anindicator for undesirable EO ingress in a chamber 230 of a syringe. Forexample, as set forth in the background, testing of samples prior toundergoing a EtO sterilization process, yielded a baseline pH, wellwithin the USP range of 4.5-7.0. However, once those prior art sampleswere subjected to prior art EtO sterilization techniques, the pH shiftedoutside the UPS range, thereby revealing that the solution within thesyringes had been altered.

The USP also sets forth an acceptable pH range for other injectablesolutions that are contemplated by this disclosure, such as lidocainehydrochloride and epinephrine injections (pH in the range of 3.3-5.5),lidocaine hydrochloride injections (pH in the range of 5.0-7.0), andheparin lock flush solutions (pH in the range of 5.0-7.0).

While the above USP standard is directed to the material within thechamber 230, the syringe assembly 100 itself also is subject to maximumresidue limits. More specifically, the syringe is classified as amedical device and is subject to ANSI/AAMI/ISO 10993-7:2012 “BiologicalEvaluation of Medical Devices—Part 7: ETO Sterilization Residuals. Forthose medical devices subject to EtO Sterilization techniques, theresidual EO gas in the device must be less than or equal to 4 mg perdevice, while the residual ECH toxic by product must be less than orequal to 9 mg/device. Currently there is no standard for residual EGtoxic byproduct.

To provide a syringe assembly 100 that conforms to the above FDArequirements, as well as the relevant ISO standards, as explained infurther detail below, the syringe assembly 100 provides that the chamber230 is capable of creating an effective barrier between sterilizationgases and the solution so that the solution remains substantiallyunchanged within the chamber 230 during and after sterilization. Forexample, in one exemplary arrangement, by the term “substantiallyunchanged,” the pH of the solution stays with the range of about4.5-7.0. The inventors of the present application have determined thatsmall shifts of the pH of the solution that results in apost-sterilization pH still within the range of about 4.5-7.0 isindicative that the sterilization technique has not caused ingress ofEtO gas into the solution via any known entry points and pathways(through the barrel, any rubber interfaces, any silicone lubricant,interface areas (tip cap)) of the assembly 100 and has therefore notadversely affected the solution contained within the chamber 230. Thus,the solution remains within acceptable specifications for themanufacture, sale, and use of the device. The inventors have discoveredthese unexpected results after numerous experiments with differentplastic material for assembly 100, in combination with variations ofsterilization cycle parameters, which will be discussed below in furtherdetail. As another example, if the solution remains substantiallyunchanged after exposure to sterilization, then the device and solutionstill meets the regulatory requirements for the manufacture, sale, anduse of that drug, i.e., is also has residual EO gas and ECH toxicbyproduct that does not exceed 10 ppm and the residual EG toxicbyproduct that does not exceed 20 ppm.

In an exemplary configuration of the syringe assembly 100, the plunger110, as shown in FIGS. 1-3, may include a plunger body 130 extendingalong an axis A and having a base 120 at one end and a stopper mount 125disposed at the opposite end of the plunger body 130. The stopper mount125 is configured to receive a plunger stopper 127. The plunger body 130may be made of a light-weight material. As explained in further detailbelow, because the plunger body 103 does not come into contact with thesolution disposed in barrel 230, there are several options for thematerial for the plunger body 103. In one exemplary arrangement, theplunger body 103 may be fabricated from polypropylene, which is low incost, as well as being lightweight.

In one exemplary configuration, the stopper mount 125 comprises anextension element 131 that extends distally from the plunger body 130.Extension element 131 has a diameter that is slightly smaller than thediameter of the plunger body 130. A mounting flange 133 is secured tothe distal end of the extension element 131. This configuration providesa mounting channel 135 between the mounting flange 133 and the distalend of the plunger body 130. Mounting channel 135 is configured toreceive an annular retainer 155 of the stopper 127, as shown in FIG. 2,for example.

As shown best in FIG. 3B, the stopper 127 may include a cylindricalportion 140 and an end portion 145, which may have a conical shape. Thecylindrical portion 140 may also include at least one wiper 150extending radially around the cylindrical portion 140. As discussedabove, in one exemplary arrangement, the stopper 125 may be connected tothe extension element 131 of the plunger body 130 via a retainer 155. Inone exemplary arrangement, the attachment mechanism 155, as shown inFIG. 3B, includes an annular retainer 155 that extends inwardly from anoutside surface and is configured to be frictionally engaged within themounting channel 135 of the extension element 131. However, it isunderstood that other connection arrangements are contemplated. Forexample, a suitable attachment member may include a male and femaleconnection mechanism, whereby the stopper 125 may define an opening (notshown) configured to receive a post (not shown) extending outwardlyalong the axis A of the plunger body 130 so as to frictionally engagethe stopper 125. Further, a suitable attachment mechanism 155 may alsoinclude an adhesive such as glue may be used. Additionally oralternatively other mechanisms may be used such as a screw mechanism,hook and eye mechanism, etc.

The stopper 125 may have relatively a stiff elastic modulus and beformed from one or more materials, including high barrier thermoplasticelastomers. Exemplary elastomers may include, but are not limited to,butyl rubber or bromobutyl rubber. The stopper 125 may also be coatedfor increased barrier properties to EO ingress, such as, for example,with silicone lubricant of appropriately selected centistokes viscosity.In addition, a suitable coating may provide smooth operating/slidefriction, with no unintended plunger movement during the manyenvironmental pressure changes imparted on the assembly 100 during thevarious EtO sterilization cycle parameters.

The base 120 of the plunger 110 may be formed so as to be co-extensivewith the plunger body 130 and thus include similar materials. In oneexemplary arrangement, the plunger body 130 is configured to angleinwardly from a first diameter D₁ to a second D₂ to a second diameter atthe proximal end 129 of the plunger body 130. This configuration servesto limit movement of the plunger body 130 within the barrel 105. Thebase 120 is sized to be greater than the first diameter D₁ so as toprovide a land area for activating movement of the plunger 130 withinthe barrel 105 during use. As explained above, during sterilization, thebase 120, and at least a portion of the plunger body 130 may be exposedto EtO gases. However, the plunger body 130 and base 120 does not comeinto contact with the sterilization sensitive material within thechamber 230. Thus, at least one of the base 120 and plunger body 130 maybe formed of less expensive plastics such as polypropylene orpolycarbonate.

The barrel 105, as shown in FIGS. 2 and 4A, includes a first end 180, asecond end 185 and a barrel body 190 extending therebetween. The barrelbody 190 may form a cylindrical shape extending along the axis A. Thefirst end 180 may be an open end configured to receive the plunger 110so as to provide a fluid tight seal. The second end 185 may include abarrel neck 195. In one exemplary arrangement, the neck 195 may includea male luer 200 defining an opening 205.

The barrel 105 may also include a mechanical engagement system, orbarrel flange 210, extending radially inwardly of an inner surface ofthe barrel 105 adjacent the first end 180. More specifically, as shownin FIG. 4A, the inner surface of the barrel 105 adjacent the first end180 of the barrel 105 may have a cross-sectional thickness that isgreater to as to extend toward a central axis extending through thebarrel 105. With this arrangement, a barrel flange 210 is formed. DuringEtO sterilization, a positive pressure differential may be createdwithin the barrel 105 (relative to the pressure outside the barrel,which may be negative). This differential may apply a force against theplunger 110, attempting to force the plunger 110 out of the barrel 105,and leaking fluid from the barrel 105. The barrel flange 210 may beconfigured to engage the outer periphery of a plunger flange 170 and/orthe wipers 150 of the stopper 125 to prevent the plunger 110 fromcomplete expulsion from the barrel 105. Other exemplary mechanicalengagements may include one or more protrusions on an inner surface ofthe barrel 105 that are sufficient to prevent expulsion of the plunger115. For example, as shown in FIG. 4C, in one arrangement, the interiorsurface of barrel 105 may further include an inwardly extending annulardetent 210′.

The stopper 125 has an outer diameter that is slightly larger than theinterior diameter of the barrel 105. While stopper 125 will compresswhen introduced into the barrel 105, the barrel flange 210 or annulardetent 210′ will prevent stopper 125 from being extracted from thebarrel 105, as portion of the annular retainer 155 will come intocontact with the barrel flange 210 and annular detent 210′.

In one exemplary method, an air bubble is intentionally left within thebarrel after filling the chamber 230 with solution. The air bubblefacilitates a large pressure differential and outward force of theplunger 110 during sterilization as an EtO sterilization cycle uses adeep draw vacuum. In another exemplary method, the chamber 230 is freeof air bubbles. As described above, choice of silicone lubricantparameters may also affect plunger motion.

Disposed on the first end exterior of the barrel 105 is a grippingflange 235. The gripping flange 235 extends radially outwardly aroundthe open first end 180 so as to be sized to be greater than a diameterof the barrel 105. In one exemplary arrangement, the gripping flange 235extends all the way around the open first end 180. In another exemplaryarrangement, the gripping flange 235 is configured with gaps betweenland areas. Both configurations allow a user to grip the barrel 105while the plunger 130 is being moved inwardly within the chamber 230.

The barrel 105 may be manufactured with one or more plastic materials.However, in one exemplary arrangement, barrel 105 is formed of cyclicolefin polymer (COP) and/or cyclic olefin copolymer (COC) materials.These polymers are similar to glass in that they have high gasimpermeability, high moisture barrier and low absorption rateproperties. However, unlike glass, COC and COP materials are not fragileand do not have the weight and transport issues associated with glass.The barrel 105 may be coated with materials for increased barrierproperties, such as silicone dioxide or aluminum dioxide. In anotherembodiment, the barrel 105 may be uncoated. Additionally oralternatively, the barrel 105 may be formed from materials having highclarity so that contents of the barrel may be visibly inspected. Thebarrel 105 may also be formed from materials having at least one of lowwater vapor permeability (in one example, less than about 0.5 g/m² perday per 330 micron thickness at atm to minimize moisture transmissionacross walls of the container), low oxygen permeability (in one example,less than about 500 cm³/m² per day per 80 micron thickness at atm tominimize gas transmission across walls of the container), high heatresistance to withstand temperatures of autoclaving (in one example, theheat resistance is effective to standard autoclaving temperatures), andminimal leaching, elution, extraction, absorption or adsorption.

The barrel 105 may be configured to receive the plunger 110 at thebarrel first end 180. The stopper 125 of the plunger 110 may be insertedat the first end 180. The stopper 125, along with the tip cap 115, maybe configured to create the chamber 230 within the barrel 105. Asexplained above, the stopper 125 may have a relatively stiff elasticmodulus and the wipers 150 may create a mating surface with the insideof the barrel 105. Thus, the stopper 125 may permit the plunger 110 tomove along axis A within the barrel 105 and also create a seal withinthe barrel 105 to prevent any material from leaving the chamber 230.Moreover, the mating conical surfaces between the barrel 105 and thestopper 125 may also serve to prevent blood uptake after the prefilledsyringe has been administered to a patient by preventing the plungerassembly 110 from recoiling upward after administration.

Referring to FIGS. 6A-7B, in one exemplary arrangement, the tip cap 115may be configured as a female luer 220 configured to receive the matingmale luer 200 extending from the barrel 105. The tip cap 115 may beconfigured to seal the syringe assembly 100 to assist in creating thechamber 230 within the barrel 105. In one exemplary arrangement, the tipcap 115 includes an insert 300 that is disposed in a housing member 302.The housing member 302 may be constructed of a substantially rigidmaterial, such as polycarbonate or other suitable plastic, as thehousing member 302 does not contact the material disposed within thechamber 230. The insert 300 includes a base member 304 and a neck 306.The base member 304 is disposed within a cavity 308 formed by innerflanges 310 that extend inwardly from an inner surface 312 of thehousing member 302. In one exemplary arrangement, the inner flange 310has an upwardly extending lip 314 that extends annularly around theinsert 300 so as to lock the insert 300 into the housing member 302. Theinner flanges 310 are separated from one another such that a void area316 is created between adjacent flanges 310. While not shown, in oneexemplary arrangement inner surface 312 may include threads.

The insert 300 is manipulated such that the base member 304 is disposedwithin the cavity 308 and retained within the housing member 302 by theinner flanges 310. With the insert 300 mechanically fixed to the housingmember 302, the housing is disposed over the barrel neck 195, such thatthe insert 300 is inserted into the barrel neck 195 with the male luer200 being received within a channel 318 of the insert with aninterference fit. A locating member 320 is disposed within an openingformed within the male luer 200. The base member 304 fits against andseals a top surface of the barrel neck 195. In one exemplaryarrangement, the inner surface 312 may include threads that cooperatewith corresponding threads disposed on an exterior surface of the barrelneck 195 to lock the tip cap 115 onto the barrel 105.

As explained, the chamber 230 may be configured to hold thesterilization-sensitive material. Thus, a portion of the tip cap 115 maycome in contact with the material during sterilization, shipping andstorage of the syringe. In instances where a syringe assembly 100 isincluded in a package such as a surgical kit, a needle for insertioninto the barrel neck 195 may also be included in the kit.

The tip cap 115 may be made of any number of materials. Exemplarymaterials may include polycarbonates that possess adequate barrierproperties. For example, plastics such as polypropylene coated with ahigh-barrier material (e.g., butyl rubber) on at least a portion of thetip cap 115 may be used. The surface area of the tip cap 115 exposed tothe material in the chamber 230 is relatively small compared to that ofthe barrel 105 and stopper 125. Thus, the portion exposed to thematerial may be coated, while the remaining portions of the tip cap 115may not.

In another exemplary arrangement (not shown), the tip cap may beconstructed entirely of butyl rubber and include a neck and a basemember. The base member is configured with an outer diameter that islarger than an outer diameter of the neck area. Disposed within the neckarea is a channel, similar to channel 318. The channel is also definedby an open end and a closed end. A locating element, similar to locatingmember 320 and may be fixedly disposed on the closed end of the channel.

In operation, the neck area is inserted into the barrel neck with themale luer being received within the channel with an interference fit.The locating member is disposed within an opening formed within the maleluer 200. The base member fits against and seals a top surface of thebarrel neck 195.

Referring to FIGS. 7A and 7B is another exemplary arrangement; the tipcap 115″ includes a butyl rubber insert 300 that is disposed in ahousing member 302. The housing member 302 may be constructed of asubstantially rigid material, such as polycarbonate or other suitableplastic, as the housing member 302 does not contact the materialdisposed within the chamber 230. The insert 300 includes a base member304 and a neck 306. The base member 304 is disposed within a cavity 308formed by inner flanges 310 that extend inwardly from an inner surface312 of the housing member 302. In one exemplary arrangement, the innerflange 310 has an upwardly extending lip 314 that extends annularlyaround the insert 300 so as to lock the insert 300 into the housingmember 302. The inner flanges 310 are separated from one another suchthat a void area 316 is created between adjacent flanges 310. While notshown, in one exemplary arrangement inner surface 312 may includethreads.

FIG. 5 shows an exemplary vial 240 including a stopper 245 and a cap250. The vial 240 may be formed from COC or COP and the stopper 245 mayinclude a region formed of a thermoplastic elastomer such as a butylrubber. The stopper 245 may be fitted within a neck of the vial 240. Thecap 250 may surround the top of the vial 240. The vial 240 may includesterilization sensitive material, similar to the syringe assembly 100above. During sterilization, pressure may build within the vial and thecap 250 may be configured to abut at least a portion of the stopper 245at the top of the vial to prevent the stopper 245 from being ejectedfrom the vial 240 during pressure increases.

As explained above, the outside of the syringe assembly 100 and/or thevial 240 may be sterilized along with the other items within a surgicalkit via a variety of sterilization techniques such as EtO sterilizationand/or autoclaving. Prior to sterilization, the separate components ofthe syringe assembly 100 and the vial 240 (e.g., the barrel 105, plunger110, tip cap 115, etc.) may be manufactured in a clean room environment.Additionally or alternatively, each component may be sterilized prior toassembly. Upon partial assembly of the components, the chamber 230 maybe filled with the material. In one example, the stopper 125 of theplunger 110 may be inserted at the first end 180 of the barrel 105 andprior to attaching the tip cap 115 to the barrel neck 195, the materialmay be filled at the opening 205. The tip cap 115 may then be attachedto the barrel 105 at the barrel neck 195, thus sealing the materialwithin the chamber 230. In another example, the tip cap 115 may first beconnected to the barrel neck 195 via the luer fitting and the materialmay be filled at the first end 180 prior to the plunger 110 beinginserted into the barrel 105. Once the chamber 230 has been filled, andthe plunger 110 inserted, the syringe assembly 100 may be sterilized.

For example, the assembly 100 may be placed in an autoclave. Bysubjecting the syringe assembly 100 to highly saturated steam, theexterior of the assembly may be sterilized. Further, the interior of thecomponents, which will not be exposed to the steam, will also besterilized due to high temperature of the container's solution therein.Once the syringe assembly 100 is removed from the autoclave, the outsideof the assembly 100 may become non-sterile; however, the fluid and fluidpath remain sterile. The syringe assembly 100 may be individuallypackaged (as single dose syringes or multiple syringes in a singlepackage) or be combined with the remaining kit contents. The individualpackages or the entire kit may then be sterilized via EtO sterilization.Thus, the outside of the assembly 100 is sterilized. For thosearrangements that include packaging the syringe assembly 100 with therest of the kit items, the outside of the assembly 100 may be sterilizedsimultaneously with the other kit components. Due to the specificproperties of the barrel 105, plunger 110, stopper 125, and tip cap 115,the material within the chamber 230 is not altered or affected by thesterilization process.

In another alternative arrangement, once the syringe assembly 100 isremoved from the autoclave, the syringe assemblies 100 (with or withoutsterilization sensitive material being disposed therein) may be placedin its own pouch with one or more vials 240 containing sterilizationsensitive material. The packaged combination syringe assembly 100 andvial 240 may then be subjected to an EtO sterilization procedure.Finally, it is understood that the present disclosure also contemplatesthat vials, such as vial 240, that are constructed of COP or COCmaterial with a suitable butyl rubber boundary, may be individuallypackaged (or included in a surgical kit) and subjected to an EtOsterilization process without adversely affecting sterilizationsensitive material.

Advantageously, prefilled container systems may be packaged togetherwith other materials requiring terminal sterilization as part of themanufacturing process and need not be separately packaged with materialshaving high barrier properties such as sealed, foil wrapping.

The inventors have found that by using COP or COC for the barrel of thesyringe and employing a suitable sterilization protocol, no undesirablepH shift of the solution disposed within the chamber 230 afterundergoing a suitable terminal sterilization procedure was experienced.More specifically, the inventors have developed a series ofsterilization protocols that were tested on an exemplary arrangement ofprototypes manufactured with a COP barrel and a tip cap manufacturedfrom polypropylene with a chlorobutyl rubber insert.

One exemplary EtO sterilization cycle that the inventors have developedfor successfully EtO sterilizing prefilled syringes has many processes,but generally can be classified into four basic groups of processesand/or parameters: 1) preprocessing or preconditioning; 2) chamberwashes and conditioning; 3) sterilization and 4) evacuation. A firstembodiment of the preprocessing group of processes/parameters for anexemplary EtO sterilization cycle is set forth in Table 1 below:

TABLE 1 Cycle Set Tolerance Category Cycle Phase Points RangePreprocessing Minimum Temp. prior to N/A 40-125° preconditioning F.Preprocessing Preconditioning Temp. 100° F. 90-130° F. PreprocessingPreconditioning Humidity 60% 45-95% Preprocessing Preconditioning Time(Hrs) N/A 6-96  Preprocessing Product % Relative humidity N/A 45-85%Preprocessing Product Temp. N/A 45-125° F.

The preprocessing group of processes is designed to precondition thesyringes to get any bacteria “active” or “excited” so as to make anybacteria/microorganisms grow and be more susceptible to EtO gas. To dothis, the preprocessing group of processes seeks to raise thetemperature and humidity to precondition the syringes and theircontents. In one embodiment, the preprocessing group of processes startsby placing the syringes in a preconditioning area, such as, for example,a room or chamber, which is set at a minimum temperature. Alternatively,the preprocessing step may also be done in a sterilization chamber,which is used for other of the parameters of the sterilization cycles,as will be explained in further detail below. In one exemplaryarrangement, the minimum initial starting temperature may be within therange of 40-125° F. In one particular example, the initial startingtemperature may be room temperature, i.e., approximately 70° F.

From the initial starting temperature, the temperature in thepreprocessing area is then raised to a preconditioning temperature. Inone exemplary arrangement, the range of temperatures is within about90-130° F. In another exemplary arrangement, the range ofpreconditioning temperatures may be within the range of 90-110° F. Inone particular example, the preprocessing temperature is set to 100° F.

The humidity is also raised in the preprocessing group of processes.More specifically, the preconditioning humidity in the preprocessingarea is raised to be in the range of 45-85% relative humidity. Inanother exemplary arrangement, the preconditioning humidity is raised inthe range of 45-95%. In one particular example, the preconditioninghumidity is set to be 60%.

To appropriately grow any bacteria/microorganisms, the syringes remainin the preprocessing area/chamber for a preprocessing time period. Thetime period is dependent upon the temperature of the product and thehumidity of the product reaching the approximate temperature andhumidity of the room/chamber. In one exemplary arrangement, the range oftime for the syringes to remain in the preprocessing room/chamber isbetween 6 hours and 96 hours. In another exemplary arrangement, therange of time for the syringes to remain in the preprocessingroom/chamber is between 18-96 hours. Before the syringes are subjectedto sterilization processes, (and may be moved to the sterilizationchamber, as explained in further detail below), the temperature of thesyringes is in the range of 45-125° F. In another exemplaryconfiguration, after preconditioning, the syringes are ±in the range of90-110° F.

Additionally, after preconditioning, in one exemplary arrangement, therelative humidity of the syringes is within the range of 45-85%. Inanother exemplary arrangement, the relative humidity of the syringes iswithin the range of 45-95%.

Once the preprocessing group of processes/parameters is complete, ifnecessary, the syringes are then exposed or subjected to chamber washesand conditioning. A first embodiment of chamber washes and conditioninggroup of processes/parameters for an EtO sterilization cycle is setforth in Table 2 below:

TABLE 2 Cycle Set Tolerance Category Cycle Phase Points Range Washing/Process Temperature 115° F. 85-130° F. Conditioning Washing/ InitialEvacuation 6 inHgA 1.0-24.0 Conditioning inHgA Washing/ Leak TestChamber 5 min. 5-60 min. Conditioning Washing/ Inject pressure changeN/A .5-3.0 Conditioning inHgA Washing/ Dwell pressure N/A 2.3-14Conditioning inHgA Washing/ Dwell time N/A 15-120 Conditioning min.Washing/ Relative humidity at end N/A 47.6-91.9% Conditioning of dwelltime Washing/ N2 Pressure 28.0 inHgA up to 30.5 Conditioning inHgAWashing/ Second Evacuation 6 inHgA 1.0-24.0 Conditioning inHgA Washing/Repeat N2 evacuations 2 0-4   Conditioning Washing/ Inject pressurechange 1.5 inHgA 0.5-3.0 Conditioning inHgA Washing/ Dwell pressure 6.5inHgA 2.3-14.0 Conditioning inHgA Washing/ Dwell time 75 min. 15-120Conditioning min.

The washing/conditioning group of processes/parameters is performed toremove most (in one exemplary arrangement >97%) of the air from thechamber so the EO gas/air mixture is not explosive. In addition, thewashing/conditioning group of processes/parameters is performed to addboth moisture and heat to the area/chamber so when EO gas is injectedinto the chamber, the bacteria/microorganisms exposed in thepreprocessing step above will be eradicated. Once the syringes areproperly sealed in a suitable area, the temperature with thearea/chamber is raised to a sterilization temperature. In one exemplaryarrangement, the sterilization temperature is raised within the range of85-130° F. In another exemplary arrangement, the sterilizationtemperature is raised within the range of 105-125° F. In yet anotherexemplary arrangement, a target temperature for the sterilizationtemperature is 115° F.

Simultaneous with raising the temperature to a sterilizationtemperature, the sterilization area is subjected to an evacuationprocess to remove air from the syringes. In one exemplary arrangement,the evacuation process applies vacuum pressure within a range of 1-24inHgA. In another exemplary arrangement, the initial evacuation processapplies vacuum pressure of approximately 6 inHgA. In yet anotherexemplary arrangement, the initial evacuation process applies vacuumpressure of approximately 10 inHgA. An acceptable tolerance for vacuumpressure is 0.5 inHgA.

Once the evacuation process reaches a desirable set point, for example10 inHgA, the vacuum may be turned off and a leak test is performed toverify that the that the sterilization area is properly sealed. If theevacuation pressure remains at the set point, within an acceptabletolerance for the duration of the leak test, then thewashing/conditioning process proceeds to a pressure injection step.However, if the leak test fails, the sterilization area must beinspected for any failed seals and preprocessing procedure must berepeated for the syringes. In one exemplary arrangement, the leak testis performed within the range of 5-60 minutes. In one particularexample, the leak test is performed for 5 minutes.

If the leak test is satisfactory, in one exemplary optional embodiment,moisture may be introduced into the syringes, such as by raising therelative humidity of the sterilization area until pressure within thesterilization area is raised to a predetermined pressure limit or thedesired relative humidity set point is reached from direct measure(i.e., if the sterilization area includes one or more sensors toindicate the relative humidity). If the pressure injection step isomitted, the next step in the process is injecting Nitrogen gas into thesterilization area, discussed below.

For the humidity injection, in one example, the sterilization area(including the syringes) is injected with moisture to a target range ofrelative humidity of 0.5-3.0 inHgA to achieve a predetermined dwellpressure. In one exemplary arrangement, the dwell pressure may be withinthe range of 2.3-14.0 inHgA. Once the desired dwell pressure is reached,the relative humidity level is maintained for a predetermined dwelltime. In one exemplary arrangement, the dwell time is within the rangeof 15-120 minutes. Once the dwell time has expired, the relativehumidity of the sterilization area is confirmed. A relative humiditywithin the range of 47.6-91.9% has been determined by the inventors tobe acceptable. If pressure injection fails, the cycle will be aborted.

After the humidity injection (or after the leak test if the humidityinjection is omitted), next, Nitrogen gas is injected into thesterilization area under pressure. In one exemplary arrangement,Nitrogen gas is injected up to 30.5 inHgA. In another exemplaryarrangement, Nitrogen gas is injected at approximately 28 inHgA. Inanother exemplary arrangement Nitrogen gas is injected with a range of26-27 inHgA.

Next, the sterilization area undergoes another evacuation process. Inone exemplary arrangement, the sterilization area is subjected to vacuumpressure within the range of 1-24 inHgA. In another exemplaryarrangement, the sterilization chamber is subjected to a vacuum pressureset point of approximately 6 inHgA. In another exemplary arrangement,the sterilization area is subjected to a vacuum pressure set point ofapproximately 10 inHgA. The inventors have determined that a toleranceof 0.5 inHgA is acceptable for the second evacuation process.

After the Nitrogen evacuation process, the Nitrogen pressure/evacuationprocess outlined above may be repeated, though not required. Forexample, in one exemplary arrangement the Nitrogen pressure/evacuationprocess is repeated within the range of 1-4 times. In another exemplaryarrangement, the Nitrogen pressure/evacuation process is repeatedapproximately 2 times. In another exemplary arrangement the Nitrogenpressure/evacuation process is repeated is repeated 3 times.

After the Nitrogen evacuation process, more water vapor may beintroduced into the sterilization area to raise the relative humiditylevel. In one exemplary arrangement, the sterilization area (includingthe syringes) is injected with moisture to a target range of relativehumidity of 0.5-3.0 inHgA. In another example, the sterilization area isinjected with moisture to a target humidity of 1.5 inHgA, to achieve apredetermined dwell pressure. In one exemplary arrangement, the dwellpressure may be within the range of 2.3-14.0 inHgA. In another exemplaryarrangement, a target dwell pressure may be within the range of 10-14inHgA. In yet other exemplary arrangements, a target dwell pressure maybe 6.5 or 11.5. Once the desired dwell pressure is reached, the relativehumidity level is maintained for a predetermined dwell time. In oneexemplary arrangement, the dwell time is within the range of 15-120minutes. In another exemplary arrangement, a dwell time of 75.0 minuteshas been found to be acceptable.

Once the chamber washes and conditioning group of processes is complete,the syringes are then subjected to an EtO sterilization process. A firstembodiment of the EtO sterilization group of processes and parametersfor an EtO sterilization cycle is set forth in Table 3 below:

TABLE 3 Cycle Set Tolerance Category Cycle Phase Points Range EtOSterilization EtO injection 20 inHgA 10.7-29.9 inHgA EtO SterilizationEtO Concentration after 710 mg/L 150-800 EtO injection mg/L EtOSterilization Nitrogen blanket 27 inHgA 25.5-30 inHgA EtO SterilizationSterilization dwell time 4 hours 1-24 hours EtO SterilizationSterilization dwell 102° F. 102-140 temperature EtO Sterilization EtOSupplement 1  0-10

The EtO sterilization group of processes begins by introduction of EtOgas into the sterilization area until reaching a predetermined pressurelevel. In one exemplary arrangement, the pressure level is within therange of approximately 10.7-29.9 inHgA. In another exemplaryarrangement, a target pressure level is 20 inHgA. In yet anotherexemplary arrangement, a target pressure level is 19 inHgA.

Next, the EtO concentration within the sterilization area is verified tobe with a preset target level after EtO injection. In one exemplaryarrangement, a suitable target range is 150-800 mg/L. In anotherexemplary arrangement, a target range of approximately 315-474.5 mg/L.In one exemplary arrangement, a set target of 421.7 mg/L is desirable.Alternatively, a biologic indicator may be used to verify the EtOconcentration within the sterilization chamber.

Once the EtO concentration has been reached, a nitrogen blanket may beintroduced. In one exemplary arrangement the nitrogen blanket targetrange is up to 30 inHgA. In another exemplar arrangement, a suitabletarget range may be between 25.5-27.0 inHgA.

The EtO concentration within the sterilization area is maintained at aset temperature for a suitable dwell time. In one exemplary arrangement,the dwell temperature is within the range 102-140° F. Alternatively, thedwell temperature may be within the range of 110-125° F. The dwell timemay be within the range of 1-24 hours. In another example, the dwelltime may be within the range of 4-8 hours. In yet another exemplaryarrangement, a dwell time of 4 hours is utilized.

During the dwell time, if the EtO concentration falls below apredetermined set point, additional EtO supplements may be injecteduntil the EtO concentration can be maintained above the set point for aminimum dwell time. EtO injections may be employed up to 10 times duringan EtO sterilization procedure.

Once the EtO sterilization group of processes is complete, the syringesare then subjected to a wash and post exposure process. A firstembodiment of the wash and post exposure group of processes/parametersfor an EtO sterilization cycle is set forth in Table 4 below:

TABLE 4 Cycle Set Tolerance Category Cycle Phase Points RangeWash/Exposure Evacuation 6 inHgA 1-24 inHgA Wash/Exposure Nitrogeninjection 27 inHgA up to 30.5 inHgA Wash/Exposure Repeat Nitrogen washes3 0-4 Wash/Exposure Evacuation 6 inHgA 1-24 inHgA Wash/Exposure AirInjection 27.0 up to 30.5 inHgA Wash/Exposure Repeat air washes 3 0-8Wash/Exposure Airbreak to atmosphere 28.00 Hg 27.5-ATM

The wash/exposure group of processes/parameters begins by evacuating EtOgas and Nitrogen from the sterilization area to remove EtO gas from thesterilization area. In one exemplary arrangement a vacuum pressure isapplied to the sterilization area within the range of 1-24 inHgA. Avacuum pressure of 6 inHgA has been found to be a suitable vacuum levelby the inventors of the present application. The evacuation pressure isapplied between 1 and 30 minutes.

Next, Nitrogen gas is injected into the sterilization chamber underpressure. In one exemplary arrangement, Nitrogen gas is injected up to30.5 inHgA. In another exemplary arrangement, Nitrogen gas is injectedat approximately 27 inHgA. In another exemplary arrangement Nitrogen gasis injected with a range of 27-28 inHgA. The nitrogen gas injection isperformed for 1 to 30 minutes. This process may be repeated up to 4times. In one exemplary arrangement, the Nitrogen gas injection isrepeated three times.

After completing the Nitrogen gas injections, the sterilization area isevacuated to an evacuation pressure. In one exemplary arrangement, avacuum pressure of approximately 1-24 inHgA is applied. In anotherexemplary arrangement, a vacuum pressure of 6 inHgA has been found to beacceptable. In yet another example, a vacuum pressure of 10 inHgA hasbeen found to be acceptable.

Next, the sterilization area undergoes an air wash step. Air is injectedunder pressure between up to 30.5 inHgA. In one exemplary arrangement,the pressure range for the air wash is between 27-28 inHgA. Thesterilization area is subjected to the air wash for 1 to 30 minutes. Theair washes may be repeated up to 6 times. In one exemplary arrangement,the air wash may be repeated 3 times. In another exemplary arrangement,the air wash process may be repeated 4 times.

After the air washes are completed, the sterilization area is opened tothe atmosphere and product pallets containing the prefilled syringes maybe removed and taken to an aeration facility within the manufacturingfacility, as well be explained in further detail below. Alternatively,the product pallets may remain the sterilization area. In one exemplaryarrangement, the aeration temperature within the aeration area of thefacility may be within the range of 95-120° F. The product pallets maybe aerated within the range of 24-120 hours.

Referring to FIG. 8, configurations of the sterilization protocols willnow be discussed. More specifically, the flow chart in FIG. 8 representsalternative product flow (i.e., syringes, vials or other items) forsterilization protocols discussed herein. For ease of explanation, theproduct flow will be described in the context of EtO sterilization of asyringe.

In a first arrangement, represented by solid arrow lines A, thepreprocessing/preconditioning group of processes begins with the syringe(or group of syringes) being placed in a preconditioning area within afacility. The preprocessing/preconditioning group of processes are thenall performed in the preconditioning area. Once thepreprocessing/preconditioning group of processes are completed, thesyringes are then moved to a sterilization chamber/area. Once in thesterilization chamber/area, in product flow A, the syringes aresubjected to the chamber washes/conditioning, sterilization andevacuation group of processes. Finally, the syringes may then be movedto an aeration area to aerate the syringes.

In another alternative arrangement, all of the group of processes (i.e.,preprocessing/preconditioning, chamber washes/conditioning,sterilization and evacuation, (including aeration) may be done as an“all-in-one” process in a single area or chamber. This product flow isrepresented by element B in FIG. 8.

As a further alternative arrangement, represented by dashed line C, theproduct flow comprises the preprocess/preconditioning group of processesbeing performed in a preprocessing area/chamber. Once completed, thesyringes are moved to a sterilization chamber/area, where the remaininggroups of processes are conducted (i.e, the chamber washes/conditioning,sterilization and evacuation, including aeration).

In the product flow arrangement represented by small dashed line D, thesyringes undergo the preprocessing/preconditioning group of processesand the chamber washes/conditioning and sterilization group of processesin the same location, such as in a sterilization chamber/area. Onceevacuation of the chamber/area is completed, the syringes are then movedto an aeration area in a facility.

Product flow arrangements represented by product flow paths E-H,involves repeating certain aspects of the groups of processes. Morespecifically, product flow path represented by a dot alternating with adash line E involves, first subjecting the syringes to the preprocessinggroup of steps in the preconditioning area. Next, the syringes are movedto sterilization chamber where the preconditioning group of processesare repeated and the chamber washes/conditioning, sterilization andevacuation (including aeration) group of processes are completed. Thesyringes are then moved to the aeration area in the facility and may beaerated again.

In the product flow arrangement represented by the small dotted line F,the syringes are first subjected to the preprocessing group of steps ina preconditioning area. Next, the syringes are moved to a sterilizationchamber where chamber washes/conditioning, sterilization and evacuationgroups of processes are conducted. The syringes are then moved to theaeration area in the facility and may be aerated again.

The product flow arrangement represented by long dashed lines G involvesfirst subjecting the syringes to the preprocessing group of steps in apreconditioning area. Next, the syringes are moved to a sterilizationchamber/area, where the preprocessing group of steps of repeated, andwhere the chamber washes/conditioning, sterilization and evacuationgroups of processes are conducted. The syringes are then moved to theaeration facility and may be aerated.

An additional alternative product flow arrangement is represented bydouble dot dashed line H. In this arrangement, the syringes aresubjected to the preprocessing group of steps in a preconditioning area.Next, the syringes are moved to a sterilization chamber whereby thesyringes then undergo another preprocessing/preconditioning step, aswell as subjecting the syringes to the chamber washes/conditioning,sterilization and evacuation group of steps, including aeration.

A series of test samples were prepared for verifying the effectivenessof the sterilization procedures described above. The sample size fortesting included 60 total prefilled syringe assemblies 100, divided intosix groups of 10 syringe assemblies 100. Each chamber 230 of therespective syringe assemblies 100 includes a chamber 230 of the barrel105 filed with 5 mL of saline and the tip cap 115 is secured at the endof the barrel 105. One set of 10 syringe assemblies 100 was selected asbeing the Control Samples (identified as Group 1) and set aside, withoutperforming any sterilization procedure.

A second set of 10 syringe assemblies 100 was designated as Group 2. TheGroup 2 syringes were exposed to two EtO sterilization cycles (asdiscussed in further detail below).

A third set of 10 syringe assemblies 100 was designated as Group 3. TheGroup 3 syringe assemblies 100 were exposed to steam sterilization only.

A fourth set of 10 syringe assemblies 100 was designated as Group 4. TheGroup 4 syringe assemblies 100 were exposed to steam sterilization andtwo EtO sterilization cycles (set forth below).

A fifth set of 10 syringe assemblies 100 was designated as Group 5. TheGroup 5 syringe assemblies 100 were exposed to one EtO sterilizationcycle (set forth below).

A final set of 10 syringe assemblies 100 was designated as Group 6. TheGroup 6 was exposed to steam sterilization and one EtO sterilizationcycle (set forth below).

The NaCl saline solution from each syringe in Groups 1-6 were tested forpH using an acceptable testing protocol for determining pH readings withan accuracy level of ±0.02 pH. The NaCl saline solution from eachsyringe in the Control Group (Group 1) and Groups 2, 4, and 6 weretested for EO and ECH residuals using an acceptable testing protocol,such as one using gas chromatography with a flame ionization detector.The average results of the testing for each group are set forth in Table5 table below:

TABLE 5 Residual Residual Avg. Avg. pH shift Sample # EO ECH pH (fromcontrol) Control Samples <0.8 ppm <0.6 ppm 5.53 Group 1 Group 2 <0.8 ppm<0.6 ppm 5.59 0.054 Group 3 Not tested Not tested 4.85 −0.683 Group 4<0.8 ppm <1.4 ppm 4.86 −0.691 Group 5 <0.8 ppm <0.6 ppm 5.38 −0.153Group 6 <5.4 ppm <0.6 ppm 5.17 −0.363

As can be seen from the table above, the pH shift is within acceptableranges resulting pH levels well within the USP requirements. Morespecifically, the pH for the solution in Groups 2-6 all fall within therange of 4.5-7.0. Moreover, the residual EO and ECH are also well withinthe FDA requirements. More specifically, the EO residual results arebelow the limit of 4 mg/device and the ECH residual results are belowthe limit of 9 mg/device.

The present disclosure provides a manufacturing methods, EtOsterilization processes and cycles, parameters, and ranges, forregulatory compliant production and EtO gas sterilization (post fillingand autoclaving) of polymer prefilled containers, such as syringes, aswell as vials. Suitable materials for such prefilled containers include0.9% NaCl normal saline, heparinized saline, or other liquids. Correctapplication of the above complex methods create resultant sterileprefilled container without EtO gas ingress to EtO sensitive fluidwithin the container. The methods disclosed herein do not create themany possible unacceptable side effects of EtO gas ingress, such as pHshift outside the range of 4.5 to 7.0; toxic byproducts like EO-EC-EGresiduals; 0.9% NaCl potency shift more than ±5%; alteration of contents(mL) due to plunger motion and leakage caused by an inappropriateselection of the nominal value of one or more of 30+ EtO sterilizationprocess cycle parameters. The discovery of these disclosed methods hasresulted in the ability to include non-glass pre-filled containers, suchas syringes and vials, that can safely be put unpackaged (i.e., withoutadditional user, inconvenient protective ETO barrierover-packaging-foil, etc.) into a standard breathable medical proceduresterile tray (i.e., convenience tray), kit pouch, or package with othercomponents, or individually package the containers and be subjected toEtO sterilization and directly ready for infusion when it is extractedfrom its packaging or lifted out of the sterile procedure tray by theoperating technician.

With regard to the processes, systems, methods, heuristics, etc.described herein, it should be understood that, although the steps ofsuch processes, etc. have been described as occurring according to acertain ordered sequence, such processes could be practiced with thedescribed steps performed in an order other than the order describedherein. It further should be understood that certain steps could beperformed simultaneously, that other steps could be added, or thatcertain steps described herein could be omitted. In other words, thedescriptions of processes herein are provided for the purpose ofillustrating certain embodiments, and should in no way be construed soas to limit the claimed invention.

Accordingly, it is to be understood that the above description isintended to be illustrative and not restrictive. Many embodiments andapplications other than the examples provided would be apparent uponreading the above description. The scope of the invention should bedetermined, not with reference to the above description, but shouldinstead be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled. It isanticipated and intended that future developments will occur in the artsdiscussed herein, and that the disclosed systems and methods will beincorporated into such future embodiments. In sum, it should beunderstood that the invention is capable of modification and variationand is limited only by the following claims.

All terms used in the claims are intended to be given their broadestreasonable constructions and their ordinary meanings as understood bythose skilled in the art unless an explicit indication to the contraryin made herein. In particular, use of the singular articles such as “a,”“the,” “said,” etc. should be read to recite one or more of theindicated elements unless a claim recites an explicit limitation to thecontrary.

1. A method of EtO sterilizing a prefilled syringe, comprising:assembling a syringe assembly including: inserting the plunger into thebarrel at a second end to define a chamber therein; filling a non-glassbarrel with sterilization sensitive material at a first end of thebarrel; inserting a tip cap at a first end of a barrel to seal thesterilization sensitive material within the barrel; and performing atleast one ethylene oxide (EtO) sterilization procedure cycle of theassembled syringe assembly, wherein the sterilization procedure cyclecomprises undergoing a preprocessing stage, a wash and conditioningstage, an EtO sterilization stage and a wash and post exposure process,wherein upon completing the EtO sterilization procedure cycle, aresultant pH of the sterilization-sensitive material is within anacceptable pH range as defined by the United States Pharmacopeia.
 2. Themethod of claim 1, wherein the barrel is formed of at least one of acyclic olefin polymer (COP) and a cyclic olefin copolymer (COC).
 3. Themethod of claim 1, wherein the sterilization sensitive material isintroduced into the barrel in an aseptic environment.
 4. The method ofclaim 1, wherein the prefilled syringe assembly is autoclaved prior toundergoing the EtO sterilization procedure cycle.
 5. The method of claim1, wherein the prefilled syringe assembly is subjected to a UV lightsterilization process prior to undergoing the EtO sterilizationprocedure cycle.
 6. The method of claim 1, wherein the sterilizationsensitive material is one of saline, heparinized saline and lidocaine.7. The method of claim 6, wherein the acceptable pH range is between4.5-7.0.
 8. The method of claim 6, wherein the acceptable pH range isbetween 5.0-7.0.
 9. The method of claim 6, wherein the acceptable pHrange is between 3.5-5.5.
 10. The method of claim 1, wherein a stopperis assembled to the plunger before introduction into the barrel, thestopper being manufactured of either bromobutyl or chlorobutyl rubber.11. The method of claim 1, wherein the preprocessing stage furthercomprises raising the temperature and humidity of a preconditioning areainto which the syringe is located to a predetermined level to initiategrowth of microorganisms.
 12. The method of claim 11, wherein thetemperature is within the range of 90-130° F.
 13. The method of claim11, wherein the humidity is within the range of 45-95%.
 14. The methodof claim 11, wherein a dwell time for maintaining the predeterminedlevel of the temperature and humidity is within the range of 6-96 hours.15. The method of claim 11 wherein the preconditioning area is also asterilization area where the EtO sterilization stage.
 16. The method ofclaim 15, wherein the preconditioning area is also an aeration area. 17.The method of claim 1, wherein the wash and conditioning stage includesmoving the syringe to a sterilization chamber, sealing the chamber andraising the temperature to a conditioning temperature within a range of85-130° F.
 18. The method of claim 1, wherein the wash and conditioningstage includes raising the temperature to a conditioning temperaturewithin the range of 85-130° F.
 19. The method of claim 18, furthercomprising initiating an evacuation process simultaneous with raisingthe temperature to the conditioning temperature.
 20. The method of claim19, wherein the evacuation process applies vacuum pressure within arange of 1-24 inHgA.
 21. The method of claim 19, wherein the evacuationprocess applies vacuum pressure to a set point of 10 inHgA, within atolerance of ±0.5 inHgA.
 22. The method of claim 19, further comprisingperforming a leak test for a predetermined time period within the rangeof 5-60 minutes.
 23. The method of claim 22, further comprisingintroducing moisture into a sterilization chamber to a target range of0.5-3.0 inHgA relative humidity to achieve a predetermined dwellpressure.
 24. The method of claim 23, wherein the predetermined dwellpressure is within the range of 2.3-14 inHgA.
 25. The method of claim24, wherein the dwell pressure is maintained for a dwell time within therange of 15-120 minutes.
 26. The method of claim 23, further comprisinginjecting Nitrogen gas under pressure into the sterilization chamber.27. The method of claim 26, wherein the Nitrogen gas is injected up to30.5 inHgA.
 28. The method of claim 27, wherein the sterilizationchamber is evacuated by subjecting the sterilization chamber to apressure set point within the range of 1-24 inHgA.
 29. The method ofclaim 28, wherein the injection of Nitrogen gas and the evacuation ofthe sterilization chamber is repeated up to four times.
 30. The methodof claim 28, further comprising introducing moisture into theserialization chamber to a target range of 0.5-30 inHgA to achieve apredetermined dwell pressure.
 31. The method of claim 30, wherein thepredetermined dwell pressure is within the range of 2.3-14.0 inHgA. 32.The method of claim 31, wherein the dwell pressure is maintained for adwell time within the range of 15-120 minutes.
 33. The method of claim1, wherein the EtO sterilization stage further comprises introducing EtOgas into a chamber containing the syringe until reaching a predeterminedpressure level.
 34. The method of claim 33, wherein the predeterminedpressure level is within the range of 10.7-29.9 inHgA.
 35. The method ofclaim 34, wherein a concentration level of EtO within the sterilizationchamber is measured to verify that the EtO concentration level is withina target range of 150-800 mg/L.
 36. The method of claim 34, furthercomprising introducing a nitrogen blanket in the sterilization chamberto a target range.
 37. The method of claim 36, wherein the target rangeis up to 30 inHgA.
 38. The method of claim 35, wherein the EtOconcentration level is maintained at a predetermined dwell temperaturefor a predetermined dwell time period.
 39. The method of claim 38,wherein the predetermined dwell temperature is within the range of102-140° F. and the predetermined dwell time period is within the rangeof 1-24 hours.
 40. The method of claim 39, further comprisingintroduction of additional EtO to reach the EtO concentration level ifthe EtO concentration level falls outside the target range of 150-800mg/L.
 41. The method of claim 1, wherein the wash and post exposurestage further comprises evacuating EtO gas and Nitrogen introducedduring the EtO sterilization stage by application of vacuum pressure.42. The method of claim 41, wherein the vacuum pressure is appliedwithin the range of 1-24 inHgA.
 43. The method of claim 42, wherein thevacuum pressure is applied within the range of 1 to 30 minutes.
 44. Themethod of claim 43, further comprising injecting Nitrogen gas into asterilization chamber containing the syringes under pressure up to 30.5inHgA.
 45. The method of claim 44, wherein the process of injectingNitrogen gas into the sterilization chamber is repeated up to 4 times.46. The method of claim 45, further comprising evacuating thesterilization chamber to a pressure within the range of 1-24 inHgA. 47.The method of claim 46, further comprising initiating an air wash of thesterilization chamber.
 48. The method of claim 47, wherein the air washfurther comprises injecting air under pressure up to 30.5 inHgA.
 49. Themethod of claim 48, further comprising repeating the air wash of thesterilization chamber up to four times.
 50. The method of claim 49,further comprising aerating the sterilization chamber within the rangeof 24-120 hours.
 51. The method of claim 1, further comprising placingthe assembled syringe assembly into an EtO serializable packaging withother surgical equipment, sealing the EtO serializable packaging withthe assembled syringe assembly and the other surgical equipment therein,before performing the EtO sterilization procedure cycle.
 52. The methodof claim 1, wherein upon completing the EtO sterilization procedurecycle, the residual ethylene oxide and ethylene chlorohydrin levels inthe sterilization sensitive material shall not exceed 10 ppm.
 53. Themethod of claim 1, wherein the residual ethylene glycol level in thesterilization sensitive material shall not exceed 20 ppm.
 54. The methodof claim 1, wherein the syringe is subjected to multiple EtOsterilization procedure cycles.
 55. A method of sterilizing a surgicalkit containing a prefilled syringe, comprising: inserting a syringe thatis prefilled with sterilization sensitive material disposed within anon-glass barrel into a procedure tray with other surgical equipment;sealing the procedure tray with the syringe that is prefilled withsterilization sensitive material and other surgical equipment therein;performing at least one ethylene oxide (EtO) sterilization procedurecycle of the sealed procedure tray, wherein the sterilization procedurecomprises undergoing a preprocessing stage, a wash and conditioningstage, an EtO sterilization stage and a Wash and post exposure stage,wherein upon completing the EtO sterilization procedure cycle, aresultant pH of the sterilization-sensitive material is within anacceptable pH range as defined by the United States Pharmacopeia. 56.The method of sterilizing a surgical kit of claim 52, wherein thesyringe that is prefilled with sterilization sensitive material isautoclaved prior to undergoing the EtO sterilization procedure cycle.57. A method of sterilizing a prefilled container, comprising: filling acontainer constructed of at least one of a cyclic olefin polymer (COP)and a cyclic olefin copolymer (COC) with sterilization sensitivematerial; sealing the container to create a barrier for thesterilization sensitive material; and performing at least one ethyleneoxide (EtO) sterilization procedure cycle of the sealed container,wherein the sterilization procedure comprises undergoing a preprocessingstage, a wash and conditioning stage, an EtO sterilization stage and awash and post exposure stage, wherein upon completing the EtOsterilization procedure cycle, a resultant pH of thesterilization-sensitive material is within an acceptable pH range asdefined by the United States Pharmacopeia.
 58. A method of sterilizationa prefilled container, comprising: assembling a syringe assemblyincluding: inserting the plunger into the barrel at a second end todefine a chamber therein; filling a non-glass barrel with sterilizationsensitive material at a first end of the barrel; inserting a tip cap ata first end of a barrel to seal the sterilization sensitive materialwithin the barrel; and performing at least one ethylene oxide (EtO)sterilization procedure cycle of the assembled syringe assembly, whereinthe sterilization procedure cycle comprises undergoing a preprocessingstage, a wash and conditioning stage, an EtO sterilization stage and awash and post exposure process, wherein upon completing the EtOsterilization procedure cycle, a resultant residual of Ethylene Oxidegas and Ethylene Chlorohydrine gas in the sterilization-sensitivematerial does not exceed 10 ppm.